Erythropoietin (Epo) is a primary regulator of erythropoiesis and functions by binding to its receptor (EpoR) on the surface of hematopoietic progenitor cells, followed by receptor- mediated endocytOsis of the Epo molecule. Recent research showed that Epo acts in vitro and EpoR is present on other cells such as neural cells - PC12 and SN6 cell lines; megakaryocytes; B lymphocytes and endothelial cells. Therefore, stimulation of erythropoiesis is not the exclusive physiological function of Epo. Human Epo receptor was cloned and sequenced in our laboratory. A 15 Kb clones genomic fragment was introduced into the mouse genome and 12 transgenic mouse lines were generated. Several hEpoR transgenic lines and normal mice were used for examining the tissue and developmental specificity of gene expression. Hematological parameters and tissue expression were measured in both normal and transgenic mice from different lines. Our results show that hematological parameters were within normal limits except for a suggestion of increased reticulocyte levels. Human EpoR transcripts were detected in hematopoietic tissues (bone marrow and spleen) and in the brain of transgenic mice. We further examined developmental specificity of EpoR gene in mice. In normal mice mEpoR transcripts in fetal liver were down-regulated through a peak value at day 12-13 to zero before birth. We found that endogenous EpoR transcripts were present in fetal brain and down-regulated during development. hEpoR transcripts in brain of transgenic mice demonstrated a persistent level throughout embryonic and adult stages. Based on the above discovery, to understand the biological significance of EpoR expression in brains of transgenic mice, we extended our study to the expression of EpoR in the different cell types, such as Hela (as negative control), K562, OCIM1, Human Umbilical Vein Endothelial cells, Immortalized HUVEC and Bone Marrow Endothelial cells. Human EpoR transcripts were found in HUVEC and BMEC but not the others. The transcripts of the above cells were quantitated by competitive PCR. We are now studying the localization of the EpoR within neural tissues.